PROJECT SUMMARY Our previous work and the ongoing studies of our parent grant reveal that a novel intervention, chronic activation of hypothalamic oxytocin neurons, prevents the hypertension that develops with chronic exposure to intermittent hypoxia (CIH), an animal model of obstructive sleep apnea (OSA). This treatment paradigm also restores autonomic balance, significantly reduces inflammation, and improves cardiovascular health. Our animal studies have provided a foundation for our clinical studies in which we have found that a single intranasal dose of oxytocin in patients with OSA increased their total sleep time and self-reported sleep satisfaction. Our analysis of the 8-hour polysomnography data from those studies further indicates that intranasal oxytocin reduced both the duration and oxygen desaturations of hypoxic events. These results altogether demonstrate that our novel target of activating the oxytocin network within the hypothalamus can be beneficial in reducing both the severity and deleterious widespread consequences of OSA, and that our animal work (currently supported by R01HL146169) and our treatment paradigm has high translational potential. This Administrative Supplement will examine our central hypothesis that both hypothalamic oxytocin neuron activation and intranasal oxytocin, in addition to reducing the development of hypertension during CIH, will reduce autonomic dysfunction and CNS inflammation, thereby mitigating the initiation and progression of cognitive decline and Alzheimer disease markers that occur with OSA. We will leverage new advances in the parent grant, such as hypothalamic oxytocin neuron activation and intranasal oxytocin as novel treatment targets. In this supplement, we will test, in the same groups of animals required to complete the goals in the parent grant, whether or not hypothalamic oxytocin neuron activation and intranasal oxytocin reduces amyloid beta deposition, neurofibrillary tangles, neuronal apoptosis, and cognitive decline that occurs in animals chronically exposed to CIH. We will use several core facilities, including the GW Behavioral Core for assessments of cognitive function and the GWU Imaging Core for quantification of amyloid beta deposition, neurofibrillary tangles and neuronal apoptosis to test our hypothesis. Our supplement has one overarching Specific Aim: To test the hypothesis that chronic hypothalamic oxytocin neuron activation and daily intranasal oxytocin administration will both independently reduce the amyloid beta deposition, neurofibrillary tangles, neuronal apoptosis, and cognitive decline that occurs with CIH.